US 10,882,851 B2 · 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections

Abstract

This invention provides quinazoline derivatives represented by the structural formula: (I); wherein: R2 is hydrogen, NR′R″, C1-7 alkyl, arylC1-7 alkyl or C3-10 cycloalkyl; R4 is amino, C1-7 alkyl, C2-7 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, aryl, heterocyclic, arylalkyl, heterocyclic-substituted C1-7 alkyl or C3-10 cycloalkyl-C1-7 alkyl; R5 is hydrogen or C1-7 alkyl, or R5 and R4 together with the nitrogen atom to which they are attached form a heterocyclic ring; Y is a single bond, C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene; R6 is halogen, heteroaryl or aryl; R′ and R″ are each independently hydrogen, C1-7 alkyl-carbonyl or C1-7 alkyl; provided that R4 is not phenyl substituted with morpholino when R2 is H and R5 is H, and provided that when NR4R5 is piperazinyl, said NR4R5 is either non-substituted or substituted with methyl or acetyl; a pharmaceutically acceptable addition salt, a stereoisomer, a mono- or a di-N-oxide, a solvate or a pro-drug thereof, for the treatment of viral infections.

A compound represented by the structural formula (I)

wherein,
R2 is NR′R″;
R4 is selected from the group consisting of C2-7 alkenyl;
C3-10 cycloalkyl;
C3-10 cycloalkenyl;
arylalkyl;
heterocyclic-substituted C1-7 alkyl;
and C3-10 cycloalkyl-C1-7 alkyl;
and wherein said R4 is optionally substituted with one or more R7;
R5 is hydrogen or C1-7 alkyl;
or R5 and R4, together with the nitrogen atom to which they are attached, form a 5 to 7-membered heterocyclic ring comprising a nitrogen atom and further optionally comprising at least one heteroatom independently selected from N, O and S, said ring being optionally substituted with one or more R7;
Y is a single bond;
R6 is selected from the group consisting of halogen;
fused benzo-C5-8 cycloalkyl optionally substituted with oxo;
heteroaryl and aryl, wherein said heteroaryl or aryl is optionally substituted with one or more R8;
each R7 is independently selected from the group consisting of halogen;
nitro;
hydroxyl;
sulfhydryl;
hydroxylamino;
cyano;
amino;
C1-7 alkyl;
halo C1-7 alkyl;
C2-7 alkenyl;
C2-7 alkynyl;
C1-7 alkoxy;
halo C1-7 alkoxy;
C1-7 alkylthio;
formyl;
—CO—NHR9;
—CO—NR9R9′;
—CS—NHR9;
—NR12—CO—NHR12;
—NR12—CS—NHR12;
—SO2NH2;
—NR12—SO2R11;
—NR12—COR10;
—NR12—CSR10;
alkoxyamino;
mercaptoamino;
thioalkylamino;
alkylamino;
alkenylamino;
alkynylamino;
alkylsulfoxide;
alkylsulfone;
hydroxyalkylamino;
mercaptoalkylamino;
hydrazino;
alkylhydrazino;
C3-10 cycloalkyl;
aryl optionally substituted with arylcarbonyl, aryloxy, (O,O-dialkylphosphonyl)-alkyl;
alkanoyl, halo-C1-7 alkoxy, hydroxy-C1-7 alkoxy, hydroxy-C1-7 alkyl, di-C1-7 alkyl-amino C1-7 alkyl, ω-carboxy-alkanoylamino, mono-(C3-7 cycloalkyl)aminocarbonyl, di-(C3-7 cycloalkyl)aminocarbonyl, mono-(C1-7 alkyl)aminocarbonyl, mono-(ω-dimethylamino-C1-7 alkyl)aminocarbonyl, di-(C1-7 alkyl)aminocarbonyl, mono-(hydroxy-C1-7 alkyl)aminocarbonyl, formylamino, —SO2NH2, arylamino-C1-7 alkyl, C1-7 alkylsulfonyl, heterocyclyl-carbonyl, heterocyclyl-C1-7 alkyl carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof;
and thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof;
each R8 is independently selected from the group consisting of halogen;
nitro;
hydroxyl;
sulfhydryl;
hydroxylamino;
cyano;
amino;
C1-7 alkyl;
halo C1-7 alkyl;
C2-7 alkenyl;
C2-7 alkynyl;
C1-7 alkoxy;
halo C1-7 alkoxy;
C1-7 alkylthio;
formyl;
—CO—NHR9;
—CO—NR9R9′;
—CS—NHR9;
—NR12—CO—NHR12;
—NR12—CS—NHR12;
—SO2NH2;
—NR12—SO2R11;
—NR12—COR10;
—NR12—CSR10;
alkoxyamino;
mercaptoamino;
thioalkylamino;
alkylamino;
alkenylamino;
alkynylamino;
alkylsulfoxide;
alkylsulfone;
hydroxyalkylamino;
mercaptoalkylamino;
hydrazino;
alkylhydrazino;
C3-10 cycloalkyl;
aryl optionally substituted with arylcarbonyl, aryloxy, (O,O-dialkylphosphonyl)-alkyl;
alkanoyl, halo-C1-7 alkoxy, hydroxy-C1-7 alkoxy, hydroxy-C1-7 alkyl, di-C1-7 alkyl-amino C1-7 alkyl, ω-carboxy-alkanoylamino, mono-(C3-7 cycloalkyl)aminocarbonyl, di-(C3-7 cycloalkyl)aminocarbonyl, mono-(C1-7 alkyl)aminocarbonyl, mono-(ω-dimethylamino-C1-7 alkyl)aminocarbonyl, di-(C1-7 alkyl)aminocarbonyl, mono-(hydroxy-C1-7 alkyl)aminocarbonyl, formylamino, —SO2NH2, arylamino-C1-7 alkyl, C1-7 alkylsulfonyl, heterocyclyl-carbonyl, heterocyclyl-C1-7 alkyl or heterocyclyl, wherein said heterocyclyl is optionally substituted with C3-7 alkenyloxycarbonyl, C1-7 alkyl or C1-7 alkyloxycarbonyl;
carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof;
and thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof;
R9 and R9′ are each independently selected from the group consisting of hydrogen;
C3-10 cycloalkyl optionally substituted with one more substituents independently selected from the group consisting of cyano, halogen, hydroxy, amino, C1-7 alkyl and C1-7 alkoxy;
C1-7 alkoxy;
halo C1-7 alkoxy;
C1-7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, alkylamino, cyano, dialkylamino, and heterocyclyl optionally substituted with C1-7 alkyl;
halo C1-7 alkyl;
heterocyclyl optionally substituted with C1-7 alkyl;
aryl and arylC1-7 alkyl wherein the aryl moiety is optionally substituted with one or more halogen;
or R9 and R9′ together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group;
R10 and R11 are each independently selected from the group consisting of C1-7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, cyano, halogen and hydroxy;
C1-7 alkoxy optionally substituted with one or more substituents independently selected from the group consisting of amino, alkylamino, cyano, dialkylamino, halogen, and heterocyclyl;
heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C1-7 alkyl, acylamino and oxo;
C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of amino and hydroxy;]] and amino optionally substituted with one or more substituents independently selected from the group consisting of C1-7 alkyl wherein said C1-7 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of amino, C1-7 alkylamino, cyano, dialkylamino, halogen and heterocyclyl;
R12 is selected from the group consisting of hydrogen and C1-7 alkyl, wherein said C1-7 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen and hydroxy;
R′ and R″ are each independently selected from the group consisting of hydrogen and C1-7 alkyl-carbonyl;
R15 is selected from the group consisting of C3-10 cycloalkyl, heteroaryl and aryl wherein said heteroaryl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-7 alkyl and wherein said C3-10 cycloalkyl is optionally substituted, at the carbon position adjacent to the nitrogen atom to which it is attached, with aryl or heteroaryl wherein said aryl is optionally substituted with halogen;
and
each R16 is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-7 alkyl, C1-7 alkoxy, di-(C1-7 alkyl)amino, mono-(C1-7 alkyl)amino, carboxamido, —SO2NH2, carbamoyl, —NR12—SO2R11 and phenoxy;
provided that when NR4R5 is piperazinyl, said NR4R5 is either non-substituted or substituted with methyl or acetyl,
and/or a pharmaceutically acceptable addition salt thereof and/or a stereo-isomer thereof and/or a mono- or a di-N-oxide thereof.

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4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections

Life of this patent

4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections

Life of this patent

Abstract

Claims5